Hydroxypropyl methyl cellulose hard capsules and process of manufacture

ABSTRACT

A composition for manufacture of hard hydroxypropyl methyl cellulose capsules comprising a film forming material of hydroxypropyl methyl cellulose having a methoxy content of 27.0-30.0% (w/w), and a hydroxypropoxy content of 4.0-7.5% and as a 2% weight solution, a viscosity of 3.5-6.0 cPs at 20° C., dipping compositions, process for manufacture of hard hydroxypropyl methyl cellulose capsules according to a dip coating process and hard capsule shells.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/860,316, filed Sep. 21, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/094,699, filed Dec. 2, 2013, now abandoned,which is a divisional of U.S. patent application Ser. No. 12/446,624,filed Feb. 25, 2010, now abandoned, which is a national stage entryunder 35 U.S.C. §371 of International Application No. PCT/IB07/03160,filed Oct. 17, 2007 which claims the benefit of U.S. ProvisionalApplication No. 60/863,190, filed Oct. 27, 2006, all of which areincorporated herein by reference.

The present invention relates to an aqueous composition for themanufacture of hydroxypropyl methyl cellulose (hereinafter also “HPMC”)hard capsules, a method of preparing HPMC hard capsules and hardcapsules obtained therewith.

Capsules are well-known dosage forms that normally consist of a shellfiled with one or more specific substances. The shell may be a soft or,as in this invention, a hard stable shell comprising film-formingpolymer(s) such as gelatine, modified starches, modified celluloses etc.

Hard capsules are generally manufactured by using a dip molding process.In this process, pin molds are dipped into a film forming composition.By gelling the film forming polymer on the pin, a film is formed that issubsequently dried on the pin, to obtain a capsule shells. The shellsare then stripped of the pins and cut to a desired length. Thus,capsules caps and bodies are obtained that can later be filed with asubstance and joined such that a filed capsule is obtained.

When using this type of dip molding process, it is necessary to ensurethat the dipping composition adheres to the pin surface and quicklygels, once the pins are withdrawn from the dipping bath. This avoidsthat the composition flows on the pins surface so as to achieve thedesired shell or film distribution to manufacture capsules.

When using gelatine as the film forming polymer, the dippingcompositions gel with cooling. The same gelling behaviour is shown bymixtures of methyl celluloses and gelling agents. Both these types offilm forming polymers may be processed on conventional devices formanufacturing hard gelatine capsules.

U.S. Pat. No. 2,526,683 discloses a process for preparing methylcellulose medicinal capsules by a dip coating process. The processconsists of dipping a capsule forming pin pre-heated to 40° C.-85° C.into a methyl cellulose composition maintained at a temperature belowthe temperature where gelation begins, withdrawing the pins and placingthe pins in ovens at temperatures above the gelation temperature anddrying the film. When the hot pins are dipped into the composition, thecomposition gels on the surface of the pin and as the pin is withdrawn,a film of gelled liquid of a certain thickness is formed on the pin. Thepin is then generally turned 180° to an upright position and typicallyplaced in the oven to dry. This technique is conventionally named“thermogelation”. The dry capsule is then stripped, cut to size and thebody and caps are fitted together. However, methyl cellulose isinsoluble in water under 37° C.

U.S. Pat. No. 3,493,407, discloses the use of non-thermal gellingdip-molding compositions of some hydroxyalkylmethyl cellulose ethers inaqueous solvents. The pins must be kept in rotation for more than halfan hour to obtain capsules with a regular shape.

U.S. Pat. No. 3,617,588, discloses the use of an induction heater to gelcellulose ether.

U.S. Pat. No. 4,001,211 discloses improved thermogelling compositionsbased on a blend of methyl cellulose and hydroxypropyl methyl cellulose.

The compositions and processes described above did not make it possibleto obtain high-performance manufacturing of hard capsules both withregard to speed, dissolution properties and with regard to overallquality. Similarly, capsules manufactured by combination of HPMC withgelling agents have very poor visual quality and dissolution propertiessince they are sensitive to cations and to pH.

Research is still going on into compositions with even better qualities,particularly as regards the absence of defect, the visual aspect, highperformance on filling machines, good dissolution properties and limitedconsumption of energy. Additives should be avoided as much as possible.

FIG. 1 is a graph showing the gelling temperature of one embodiment ofthe disclosed hard capsules.

It is an object of the instant invention to provide new compositionsparticularly for the manufacture of HPMC capsules of high quality: e.g.,standardized dimension, high transparency (similar to hard gelatinecapsules), and excellent dissolution and mechanical performance.

This and other objects are achieved by a first aspect of the presentinvention which is an aqueous composition for the manufacture of hardcapsules, wherein the composition comprises, in an aqueous solvent,15-25% by weight, based on the total weight of the aqueous composition,of a hydroxypropyl methyl cellulose having a methoxy content of27.0-30.0% (w/w), a hydroxypropoxy content of 4.0-7.5% (w/w) and aviscosity of 3.5-6.0 cPs as a 2% weight solution in water at 20° C.

In the present invention the HPMC methoxy and hydroxypropoxy contentsare expressed according to the USP30-NF25.

In the present invention the viscosity of the HPMC 2% weight solution inwater at 20° C. is measured according to the USP30-NF25 method forcellulose derivatives.

Preferably the aqueous composition comprises 17-23% by weight, based onthe total weight of the aqueous composition, of the hydroxypropyl methylcellulose.

Suitable hydroxypropyl methyl celluloses are commercially available. Forexample suitable types are all those fulfilling the requirements setforth in USP30-NF25 for HPMC type 2906.

Suitable aqueous compositions can be obtained by blending HPMCs of sametype but different viscosity grade.

In a preferred embodiment, the HPMC in the aqueous composition of theinvention is a HPMC having a viscosity of 4.0-5.0 cPs as a 2% w/wsolution in water at 20° C.

Viscosity of the HPMC solution in water can be measured by conventionaltechniques, e.g., as disclosed in the USP by using a viscometer of theUbbelohde type.

In an embodiment, the aqueous compositions of the invention may containbetween 0% and 5%, preferably between 0% and 2% by weight based on thetotal weight of the aqueous composition of additional non animal-derivedfilm-forming polymers typically used for the manufacture of hardcapsules. Preferably, the HPMC aqueous compositions of the inventioncontain no other film-forming polymer beside the HPMC presentlydisclosed. Non animal-derived film-forming polymers are for examplepolyvinyl alcohol, plant-derived or bacterial-derived film-formingpolymers. Typical plant-derived film-forming polymers are starch, starchderivatives, cellulose, celluloses derivatives other than the HPMC asdefined herein and mixtures thereof. Typical bacterial-derivedfilm-forming polymer are exo-polysaccharides. Typicalexo-polysaccharides are xanthan, acetan, gellan, welan, rhamsan,furcelleran, succinoglycan, scleroglycan, schizophyllan, tamarind gum,curdlan, pullulan, dextran and mixtures thereof.

In a preferred embodiment, the HPMC aqueous compositions of theinvention contain between 0% and 1%, preferably 0% by weight based onthe total weight of the aqueous composition of animal-derived materialsconventionally used for the manufacture of hard capsules. A typicalanimal-derived material is gelatin.

In a preferred embodiment, the aqueous compositions of the inventioncontain less between 0% and 1%, preferably 0% by weight based on thetotal weight of the aqueous composition of a gelling system. By “gellingsystems” it is meant one or more cations and/or one or more gellingagents. Typical cations are K⁺, Na⁺, Li⁺, NH₄ ⁺, Ca⁺⁺, Mg⁺⁺ and mixturesthereof. Typical gelling agent(s) are hydrocoloids such as alginates,agar gum, guar gum, locust bean gum (carob), carrageenans, tara gum, gumarabic, ghatti gum, khaya grandifolia gum, tragacanth gum, karaya gum,pectin, arabian (araban), xanthan, gellan gum, konjac mannan,galactomannan, funoran, and mixtures thereof. As usually, gelling agentscan optionally be used in combination with cations and other ingredientssuch as sequestering agents.

As the HPMC aqueous compositions disclosed herein are suitable to givestrong and physically stable gels without gelling systems, thedissolution properties of the HPMC capsules of the invention are notaffected by the drawbacks typically associated with gelling systems,notably cations.

At the natural state—i.e. without the addition of pigments or similaringredients in the composition—the HPMC hard capsules obtainable fromthe aqueous compositions of the invention show good clarity andtransparency. The transmittance measured by UV at 650 nm on the capsulebody (through its double shell layers) is around 80%, identical togelatine hard capsules.

For obtaining coloured capsules at least one inert non-toxicpharmaceutical grade or food grade pigment such as titanium dioxide canbe incorporated in the aqueous compositions. Generally, 0.001 to 1.0% byweight of pigment can be included in the aqueous composition. The weightis expressed over the total weight of the composition.

Optionally, an appropriate plasticizer such as glycerine or propyleneglycol can be included in the aqueous solutions. To avoid an excessivesoftness, the plasticizer content has to be low, such as between 0% and2%, more preferably between 0% and 1% by weight over the total weight ofthe composition.

The aqueous compositions of the invention can be prepared by dispersingthe HPMC and the other optional ingredients in one or more aqueoussolvents, preferably water. The aqueous solvent can be at a temperatureabove room temperature, preferably above 60° C., more preferably above70° C. Optimal temperatures can be determined by the skilled person. Ina preferred embodiment after de-bubbling, the dispersion is cooled downbelow room temperature, preferably below 15° C., to achieve thesolubilisation of the HPMC.

The gelling temperature of the aqueous compositions may be determined bya measurement of the viscosity by progressively heating the composition.The temperature at which the viscosity starts to sharply increase isconsidered as the gelling temperature. As an example, for aconcentration of about 19% w/w in water, any HPMC of the inventionfulfilling the USP definition of HPMC type 2906 has a gellingtemperature of about between 30 and 40° C. As an additional example, forconcentrations between 15 and 25% w/w in water, an HPMC of the inventionfulfilling the USP definition of HPMC with a hydroxypropoxy content ofabout 6%, has a gelling temperature between about 30 and 40° C. Anexample of how gelling temperature can easily be measured is provided inthe examples.

The aqueous compositions of the invention can be used as dippingcompositions in dip-molding processes for the manufacture of HPMC hardcapsules.

It has been noted that the aqueous compositions of the invention allowthe manufacture of good HPMC hard capsules showing optimal dissolutionproperties. Dissolution profile is a key point in therapy to obtain acomplete and reproducible release of the substance contained in thecapsule.

Additionally, it has been noted that the aqueous compositions of theinvention allow the manufacture of good HPMC hard capsules whose bodiesand caps, once telescopically joined, can suitably be sealed. This makesthe presently disclosed new HPMC hard capsules a particularly good andcost-effective solution for the manufacture of liquid-filled oral dosageforms as well as powder-filled dosage forms for inhalation or themanufacture of tamper-proof pharmaceutical forms to be used in thecontext of double-blind trials.

In a second aspect, the present invention relates to a process for themanufacture of hydroxypropyl methyl cellulose hard capsules according toa dip coating process, characterized in that it comprises the steps of.

(a) providing an aqueous composition of a hydroxypropyl methyl cellulosehaving a methoxy content of 27.0-30.0% (w/w), a hydroxypropoxy contentof 4.0-7.5% (w/w) and a viscosity of 3.5-6.0 cPs as a 2% weight solutionin water at 20° C., wherein the concentration of the hydroxypropylmethyl cellulose in the aqueous composition is chosen to obtain aviscosity of the aqueous composition of 1000 to 3000 cPs, preferably1200 to 2500 cPs, more preferably 1600 to 2000 cPs, measured at atemperature of 10° C. to 1.0° C. below the aqueous composition gellingtemperature,(b) preheating dipping pins so that they are at 55-95° C. when dippedinto the aqueous composition,(c) dipping the pre-heated dipping pins into the aqueous compositionmaintained at a temperature of 10° C. to 1.0° C. below its gellingtemperature,(d) withdrawing the dipping pins from the aqueous composition obtaininga film on the dipping pins and(e) drying the film on the dipping pins at a temperature above thegelling temperature of the aqueous composition so as to obtain moldedcapsule shells on the pins.

Steps (a) and (b) can be performed in any order. By contrast, steps (c)to (e) are to be performed in the order they are presented and aftersteps (a) and (b).

In step (a) the aqueous compositions of the invention can be used. Anoptional adjustment of the HPMC concentration can be performed to meetthe viscosity ranges indicated above.

In step (b), the temperature range of preheated pins is 55-95° C.meaning that this is the pin temperature when pins are dipped.Preferably the temperature is 60-90, more preferably 60-85° C., morepreferably 65-85° C., even more preferably 70-80*C. It is preferred thatsuch temperature be chosen according to the desired capsule size. By“according to the capsule size” it is meant that the smaller the pindimension, the higher the temperature. For example, for an HPMC type2906 (USP classification) and within the HPMC weight ranges definedabove for the aqueous composition, for a capsule size 00 (conventionallyconsidered a large capsule size), the pin temperature is preferablybetween 70 and 80, for a capsule size 1 (conventionally considered amedium capsule size), the pin temperature is preferably between 80 and90, and for a capsule size 4 (conventionally considered a small capsulesize), the pin temperature is preferably between 85 and 95.

In step (c), the dipping composition is maintained at a temperature of10° C. to 1.0° C., preferably 6° C. to 2.0° C., below its gellingtemperature. For example, if a dipping composition has a gellingtemperature of about 36.0° C., it can be maintained at a temperature offor example about 34.0° C.

After being withdrawn from the dipping composition, the pins can beturned from a “top-down” dipping position to a “top-up” drying positionaccording to conventional capsule molding processes. In this step thepins are rotated about a horizontal axis of about 180° with respect tothe dipping position of step (c).

By drying in step (e) the object is to reduce the water content in thecapsule shells on the pins. Generally, the water content in the moldedcapsule shells is reduced from around 80% to around 7% by weight, basedon the total weight of the molded capsule shells. An indicative watercontent in the capsule shell of the invention is provided below.

Step (e) can be performed according to any technique commonly known forthis purpose, for example by placing the pins in conventional ovens, fora sufficient period of time, typically from 30 to 60 minutes.

In a preferred embodiment, step (e) is performed as disclosed in theco-pending patent application, filed by the instant Applicant on Oct.26, 2006, having the title “Capsule formation” and having filing numberU.S. 60/863,040. According to such a preferred embodiment, it has beenfound that subjecting the film to a particular combination oftemperature and relative humidity provides excellent results.

Thus, preferably step (e) comprises a step (e1) where the dipping pinswith the molded capsule shells are subjected to a temperature of 50 to90° C. at a RH of 20 to 90%, preferably, T is 55 to 85° C. at a RH of 20to 70%, more preferably T is 60 to 85° C. at a RH of 20 to 60%.

Generally the duration of step (e1) is 90-480 seconds, preferably120-300 seconds, more preferably 120-240 seconds.

Step (e1) is preferably followed by a step (e2), where the pins aresubjected to a temperature of 30 to 60° C. at a RH of 20 to 90%,preferably, T is 35 to 55° C. at a RH of 20 to 70%, more preferably T is35 to 50° C. at a RH of 20 to 60%.

Generally the duration of step (e2) is 30 to 60 minutes.

Both steps (e1) and (e2) can be performed in an oven. The ovens used arepreferably tunnels which allow a continuous processing.

The term “relative humidity” is used herein to mean the ratio of theactual water vapor pressure at a given temperature to the vapor pressurethat would occur if the air were saturated at the same temperature.There are many technologies for humidity measurement instruments knownto the skilled person, all of which would give substantially the same RHmeasure.

In the current description, if not otherwise indicated, by “capsule” itis meant a hard capsule consisting of two co-axial,telescopically-joined parts, referred to as body and cap. Normally, capsand bodies have a side wall, an open end and a dosed end. The length ofthe side wall of each of said parts is generally greater than thecapsule diameter. Thus, the HPMC hard capsules of the present inventiondo not structurally depart from the conventional definition of hardcapsules. “Capsule” refers to both empty and filed capsules.

The molded capsule shells mentioned to above, generally refer to bothbodies and caps, depending on the shape of the mold pin. Thus, afterstep (e) the dried capsule shells on the dipping pins can be processedaccording to conventional steps. This means that in general after step(e), the capsule shells (bodies and caps) are stripped from the pins.This step can be followed by cutting the stripped shells to a desiredlength.

Typically, hard capsule dip-molding manufacturing processes encompass anadditional step of lubricating the pins so as to make it easier to stripthe capsule shells from the pins. Lubrication is normally achieved viathe application of a demolding agent to the pins surface.

In the instant invention any demolding agent and lubricating apparatusconventionally used for HPMC capsules can be used.

After stripping and cutting, the bodies and caps may be fitted togetherfor obtaining a complete capsule. Preferably, the capsule cap and bodyare telescopically joined together so as to make their side wallspartially overlap and obtain a capsule.

“Partially overlap” also encompasses an embodiment wherein the sidewalls of caps and bodies have substantially the same length so that,when a cap and a body are telescopically joined, the side wall of saidcap encases the entire side wall of said body. This embodiment isparticularly advantageous for the manufacture of tamper-proof capsulesto be used for example in the context of double-blind trials.

In one embodiment, the dipping pins are designed so as to createpre-locking means in caps and bodies formed thereon. Suitable pinsdesign and pre-locking means are disclosed for example in EP 110500 B1,notably lines 27-31 of column 2 and for example FIG. 34. If caps andbodies are provided with pre-locking means, the bodies and caps obtainedafter stripping, are first jointed to obtain a pre-locked capsule. Thispre-locked capsule can then be re-opened, filled and locked to its finalposition.

Once filled, the capsules can be made tamper-proof by using any solutionconventionally used in the field of hard capsules to make the jointpermanent. Banding or sealing are suitable techniques. Sealing is atechnique well known in the field of hard shell capsules. Variousalternative techniques are currently used for this purpose. A suitableprocedure is disclosed for example in U.S. Pat. No. 4,539,060 and U.S.Pat. No. 4,656,066. Many improvements of sealing procedure are currentlyavailable.

According to a know sealing process, the capsule is (i) contacted with asealing fluid, (ii) excess sealing fluid is removed from the surface and(iii) the capsule is dried so as to induce curing and make the sealpermanent.

For the HPMC capsules obtained with the invention, alcohol/watermixtures can be used as sealing fluids, such as ethanol/water mixtures.

The good sealing quality obtained makes the sealed capsule of theinstant invention particularly suitable for the manufacture ofleakage-free dosage forms particularly for use in the administration ofsubstances in liquid form. By “sealing quality” it is meant either thevisual quality and/or the adhesion strength of the sealing.

The above aqueous compositions and process are particularly suitable formanufacturing HPMC hard capsules that dissolve at a rate comparable toconventional gelatine capsules. Such capsules can be manufactured at anindustrial scale with process speeds comparable to gelatine capsules.Their mechanical properties are better than those of conventionalgelatine capsules since they are less brittle, particularly underextremely dry atmosphere. Their visual appearance is similar to that ofgelatine capsules.

In a third aspect, the present invention relates to a HPMC hard capsuleshell containing a HPMC having a methoxy content of 27.0-30.0% (w/w), ahydroxypropoxy content of 4.0-7.5% (w/w) and a viscosity of 3.5-6.0 cPsas a 2% weight solution in water at 20° C., wherein the methoxy andhydroxypropoxy contents are expressed according to the USP30-NF25 andwherein the viscosity is measured according to the USP method forcellulose derivatives.

In a preferred embodiment, the capsule shells are obtainable by theaqueous composition and/or process disclosed above.

In a preferred embodiment, the capsule shell contains the HPMC in anamount between 70 and 99%, preferably between 80 and 99% by weight basedon the shell weight. If no other film-forming polymers are present, theHPMC is preferably between 92% and 99%, more preferably between 93 and98%, even more preferably between 94% and 97% by weight based on theshell weight.

In a preferred embodiment, the capsule shell contains between 0% and25%, preferably between 0% and 10% by weight based on the shell weightof additional non animal-derived film-forming polymers as defined above.

In a preferred embodiment, the capsule shell contains water between 1 to8%, preferably between 7 and 2%, more preferably between 6 and 3% byweight based on the shell weight.

In a preferred embodiment, the capsule shell contains one or morepigments as those discussed above, between 0 and 10%, preferably between0.001 and 5%, more preferably between 0.01 and 3%, by weight based onthe shell weight.

In a preferred embodiment, the capsule shell contains one or more dyesbetween 0 and 5%, preferably between 0.001 and 3%, more preferablybetween 0.01 and 2%, by weight based on the shell weight.

In a preferred embodiment, the capsule shell contains one or moreplasticizers as those discussed above, between 0 and 10%, preferablybetween 0.001 and 5%, more preferably between 0.01 and 3%, by weightbased on the shell weight.

In a preferred embodiment, the capsule shell contains one or moreantibacterial agents between 0 and 2%, preferably between 0.001 and 1%,more preferably between 0.01 and 0.5%, by weight based on the shellweight.

In a preferred embodiment, the capsule shell contains one or moreflavourings agents between 0 and 2%, preferably between 0.001 and 1%,more preferably between 0.01 and 0.5%, by weight based on the shellweight.

In a preferred embodiment, the HPMC hard capsule shell presentlydisclosed can be used for the manufacture of tamper-proof pharmaceuticaldosage forms. To this end, it is particularly advantageous if thecapsule shell is as disclosed in EP 110500 B1. In this preferredembodiment, the HPMC hard capsule shell comprises coaxial cap and bodyeach of the cap and body having a generally cylindrical side wall, anopen end and a closed end region, the side wall of each of said parts issubstantially greater than the capsule shell diameter, the cap and bodybeing adapted to be joined in telescopic relationship wherein, when thecap and body are fully joined in telescopic relationship, the onlyportion of the body which is exposed is the closed end region, andwherein the closed end region has an outer surface which is of such aconfiguration as to resist being gripped, whereby separation of the capand body is impeded, and wherein when the cap and body are fully joinedin telescopic relationship, the inner side wall of the cap issubstantially totally overlapped by the outer side wall of the body. Inother words, when the cap and body are fully joined in telescopicrelationship, the side wall of the cap encases the entire side wall ofthe body. Thus, in use, only the body dosed end is exposed and presentsa minimal surface for gripping and withdrawal of the body from withinthe cap, thereby impeding separation of the capsule shell.

The closed end region of either the body and the cap may, for example,have a configuration which is generally hemispheroidal, pyramidal,conical or flat.

For additional security, it is preferred that the body and the capfurther include mutual locking means comprising one or morecircumferentially extending ridges and/or grooves. Thus, the capsuleshell may be such that the side wall of one of the cap and body has alocking means comprising one or more circumferentially extending ridgeextending either (i) radially inwardly from an inner surface of the sidewall of the cap or (i) radially outwardly from an outer surface of theside wall of the body, as the case may be.

Alternatively, or in addition, the side wall of the other of the cap andbody has one or more circumferentially extending groove extending either(i) radially inwardly from the outer surface of the body or (ii)radially outwardly from the inner surface of the cap, as the case maybe, and engaging a respective ridge.

It is preferred that the capsule shell further includes venting means topermit air to escape from within the capsule when joined, wherein the oreach circumferentially extending ridge comprises two or more segments sothat spaces between the segments act as vents to permit air to escapefrom within the capsule when the cap and body are being joined.

It is preferred that the side wall of one of the cap and body has a pairof diametrically opposed integral indents extending either (i) radiallyinwardly from the inner surface of the side wall of the cap or (ii)radially outwardly from the outer surface of the side wall of the body,as the case may be; and the diametric spacing of the indents is, in thecase (i), less than the outside diameter of the open end of the body or,in the case (ii), greater than the inside diameter of the open end ofthe cap, such that the body can enter the cap and permit air to escapefrom within the capsule when the cap and body are being joined.

For storage and/or transportation purposes, it is preferred that thecapsule shell may also include means for pre-locking the partiallyjoined caps and bodies in a constant predetermined relative positionprior to filing and final joining. This embodiment is particularlyadvantageous when it is desired to include step [I-1] in the process ofthe invention.

Preferably, bodies have a reduced diameter in the area of their open endin order to avoid abutment when they are telescopically housed withincaps.

Alternatively, or in addition, caps have a reduced diameter in the areaof their open end, thereby resulting in improved engagement between themand the region of the side wall of the bodies adjacent the dosed endregion of the bodies, as further resistance to tampering.

In a fourth aspect the present invention relates to a HPMC hard capsulecomprising a capsule shell as defined above and one or more substancesfilled therein.

All kinds of suitable compounds may be filed in the capsule of thepresent invention including pharmaceuticals, vitamins or nutrients,plant powder extracts etc, including particularly hygroscopicingredients.

When used as dosage form for drugs, capsules of the invention typicallycomprise for example from 0.001 g to 2.0 g of active ingredient,optionally mixed with one or more pharmaceutically acceptableexcipients.

In one embodiment, the HPMC hard capsule presently disclosed, optionallysealed, can be used in the context of dry powder inhalers (also commonlyknow by the acronym DPIs). In this embodiment, the superiority of thepresently disclosed capsules over conventional HPMC capsules can betraced back for example to:

-   -   capsules improved colour/transparency,    -   reduced stickiness of the internal surface of caps and bodies        side walls due for example to a reduced amount of demolding        agent required in capsule manufacturing process,    -   improved quality of capsule sealing.

All of the capsule embodiments disclosed above can be produced onconventional capsule-making machines utilizing dip-moulding technology.The skilled person can find additional background information ondip-moulding process for gelatine capsules in U.S. Pat. No. 4,893,721.

In a fifth aspect, the present invention relates to hydroxypropyl methylcellulose hard capsule shells and capsules as defined above, for use inthe administration to a subject of substances, particularlypharmaceutical substances, in liquid or solid form.

In a sixth aspect, the present invention relates to the use ofhydroxypropyl methyl cellulose hard capsule shells and capsules asdefined above for the manufacture of pharmaceutical dosage formssuitable for the administration to a subject of pharmaceuticalsubstances in liquid or solid form.

By “solid form” it is preferably meant powder form, and theadministration of the substance(s) may preferably entail the use of adry powder inhaler.

By “subject” it is preferably meant a human or animal subject, morepreferably a human subject.

Preferred conditions for implementing the compositions described abovealso apply to the other subjects of the invention envisaged above suchas processes and capsules.

The scope of the invention can be understood better by referring to theexamples given below, the aim of which is to explain the advantages ofthe invention. Unless otherwise specified, all parts and percentages areby weight. Composition viscosities were determined by Brookfieldviscometer.

EXAMPLE 1: AQUEOUS COMPOSITION FOR THE MANUFACTURE OF HYDROXYPROPYLMETHYL CELLULOSE HARD CAPSULES

A 5 kg composition of 18.8% HPMC type 2906 (methoxy content 28.7%,hydroxypropoxy content 5.4%) of 4.4 cPs viscosity at 2% concentration(w/w) was prepared as follows:

The HPMC powder is dispersed into hot water at 75° C. under stirring.Formation of foam is observed. After complete dispersion of the powder,the temperature is kept at 75° C. under very gentle stirring forde-foaming of the dispersion. Then the dispersion is cooled down to 10°C. under gentle stirring for obtaining dissolution of the HPMC. Afterkeeping the composition for more than 30 minutes at 10° C., a dippingcomposition ready for use in capsule manufacturing is obtained.

The HPMC composition gelling temperature was determined by viscositymeasurement by progressively heating the composition. The gellingtemperature found was 34° C.

EXAMPLE 2: MANUFACTURE OF HARD CAPSULES

The composition prepared in example 1 is poured into the dipping dish ofa pilot equipment of hard capsule manufacturing. The dip pins of size 0are pre-heated at 75° C., while the dipping composition is maintained at32° C. At this temperature, the viscosity of the dipping composition was2000 cPs. Capsules of size 0 are manufactured by the conventionaldipping process, but with the pre-heated pins. After the dipping, thecapsules are dried in an oven with hot air at 60*C and 40% RH for 3minutes then with hot air at 40*C and 40% RH.

The capsules obtained are of high quality: good and standardizeddimension (the top wall thickness is >140 μm), high transparency(similar to hard gelatin capsules), excellent dissolution and mechanicalperformance.

EXAMPLE 3: OPTIMAL ORE-HEATING TEMPERATURE FOR PINS

Example 2 was re-run but with dip pins pre-heated at 60° C. instead of75° C. It is noted that pin size 0 is considered a medium-largedimension.

The gelling on the pins after dipping was not optimal to obtaincommercially acceptable capsules. Solution partially flew down the pinduring drying, leading to the top wall thickness less than 50 μm.

Conclusion: 60° C. as pin pre-heating temperature is less preferablethan 75° C. for size 0 capsule manufacturing.

EXAMPLE 4: MECHANICAL PROPERTIES UNDER STRESS CONDITIONS OF THE CAPSULESOF EXAMPLE 2

The mechanical properties of the capsules of example 2 were tested understress conditions as follows: A stainless steel cylinder weighing 100 gwas allowed to fall from a height of 8 cm onto empty capsules one byone. The percentage of broken capsules is reported hereunder.

Results:

% of broken capsules Storage conditions RH % Capsules of example 2Gelatine capsules 2.5 0 24 10 0 13 23 0 2 33 0 0 50 0 0 RH = RelativeHumidity

Conclusions: capsules of example 2 do not exhibit any brittleness evenat extremely low relative humidity.

EXAMPLE 5: IN VITRO DISSOLUTION PERFORMANCE OF THE CAPSULES OF EXAMPLE 2

The capsules of example 2 were tested according to the USP monographmethod for dissolution of acetaminophen capsules.

Results:

Dissolution medium Time % Acetaminophen dissolved pH 1.2 15 min 32 30min 68 45 min 88 60 min 95 75 min 100 Demineralised water 15 min 36 30min 70 45 min 88 60 min 95 75 min 98 pH 6.8 potassium 15 min 29phosphate 30 min 67 45 min 87 60 min 96 75 min 99

EXAMPLE 6: DETERMINATION OF THE GELLING TEMPERATURE

A 18.8% w/w solution in water of HPMC type 2906 is prepared as describedin example 1. The viscosity is monitored with a Brookfield Model DV-IIviscometer at different temperatures by increasing the measure celltemperature by steps (with 10 minutes equilibrium at each step). Theresults are shown in FIG. 1. It can immediately be appreciated that thegelling temperature is around 34° C.

COMPARATIVE EXAMPLE 1: MANUFACTURE OF CAPSULES WITH HPMC TYPE 2910

A 5 kg composition of 26.3% HPMC type 2910 of 3 cPs viscosity at 2% wasprepared as in examples 1 and 2. The gelling temperature found was 47°C. While the dipping composition is maintained at 45° C.

Capsules of size 0 were manufactured under the same process conditionsas in the above example 2 (viscosity of the dipping composition 2000 cPsat 45° C.).

Results: an acceptable dimension is obtained (the top wall thickness isabove 140 μm). However, too brittle capsules are obtained since almostal the capsules break during their stripping from the dipping pins.

COMPARATIVE EXAMPLE 2: MANUFACTURE OF CAPSULES WITH HPMC TYPE 2910

A 5 kg composition of 17.9% HPMC type 2910 of 6 cPs viscosity at 2% wasprepared as in examples 1 and 2. The gelling temperature found was 50°C. While the dipping composition is maintained at 48° C. Capsules ofsize 0 were manufactured under the same process conditions as in theabove example 2 (viscosity of the dipping composition 2000 cPs at 48°C.).

Results: an unacceptable dimension is obtained (insufficient gellingbehaviour, composition on the pins partly flowing down, top wallthickness less than 80 μm). Therefore, the advantage in using an HPMCtype 2906 against using other HPMCs such as HPMC type 2910 can be seen.

COMPARATIVE EXAMPLE 3: MANUFACTURE OF CAPSULES WITH TOO LOW DIPPINGSOLUTION VISCOSITY

Example 2 was re-run but with a dipping solution of a viscosity at 900cPs measured at 32° C. This decrease in viscosity was obtained by addingwater to the composition.

The gelling on the pins after dipping was not sufficient, solutionflowing down occurred during the drying, leading to the top wallthickness less than 50 μm, much too low for being acceptable. Results: aviscosity of 900 cPs for the dipping solution is too low to have anacceptable gelling ability and top wall thickness.

1. A process comprising: forming hydroxypropyl methyl cellulose hardcapsules using thermogelation by: (a) providing an aqueous compositionof a 2906 hydroxypropyl methyl cellulose having a methoxy content of27.0-30.0% (w/w), a hydroxypropoxy content of 4.0-7.5% (w/w) and aviscosity of 3.5-6.0 cPs as a 2% weight solution in water at 20° C.,wherein the aqueous composition is substantially free of gelling agent;(b) dipping heated dipping pins into the aqueous composition, whereinthe aqueous composition is maintained at a temperature below a gellingtemperature of the aqueous composition, (c) withdrawing the dipping pinsfrom the aqueous composition obtaining a film on the dipping pins; and(d) drying the film on the dipping pins so as to obtain molded capsuleson the pins.
 2. The process of claim 1 wherein the hydroxypropyl methylcellulose is present in a range from 15 to 25% by weight, based on thetotal weight of the aqueous composition.
 3. The process of claim 1wherein the dipping pins are heated such that the dipping pins are55-95° C. when dipped into the aqueous composition.
 4. The process ofclaim 1 wherein the dipping pins are heated such that the dipping pinsare 60-90° C. when dipped into the aqueous composition.
 5. The processof claim 1 wherein the aqueous composition in step (b) is maintained ata temperature of 10° C. to 1.0° C. below a gelling temperature of theaqueous composition.
 6. The process of claim 1 wherein step (d)comprises (d1) exposing the pins to an environment having temperature of50-90° C. and a relative humidity of 20-90%.
 7. The process of claim 6wherein the temperature is 60-85° C. and the relative humidity is20-60%.
 8. The process of claim 6 wherein after (d1) the pins areexposed to a temperature of 30-60° C. and a relative humidity of 20-90%as step (d2).
 9. The process of claim 8 wherein the duration of step(d2) is between 30 and 60 minutes.
 10. A hard capsule formed by theprocess of claim
 1. 11. A hydroxypropyl methyl cellulose hard capsuleshell comprising: a thermogelled hard capsule shell comprisinghydroxypropyl methyl cellulose 2906, having a methoxy content of27.0-30.0% (w/w), a hydroxypropoxy content of 4.0-7.5% (w/w) and aviscosity of 3.5-6.0 cPs as a 2% weight solution in water at 20° C.,wherein the 2906 hydroxypropyl methyl cellulose is present in an amountranging from 70% to 99% by weight of the shell weight.
 12. The capsuleshell of claim 11 wherein the hydroxypropoxy methyl cellulose is presentin an amount between 70% and 90% by weight on the shell weight.